Carbamoylpyrazines

Controlled hydrolysis of the cyano groups of 58 can give any one of the three possible products the diacid 85, the amide/acid 87, or the diamide 88 in excellent yields (72GEP2216925). Decarboxylation of 87 to 3,5-diamino-6-carbamoylpyrazine (89), and its subsequent conversion to 3,5-diaminopyra-zinoic acid (90) by hydrolysis has also been demonstrated. 

Pyrazines are known to exhibit a range of physiological activities. For example, 2-carbamoylpyrazine ( pyrazinamide ) is used in the treatment of tuberculosis (138-141). In animals pyrazinamide was at least twice as active as p-aminosalicyclic... 

Vogl and Taylor (378) first utilized the reaction of amidines, namely, a-amidino-a-aminoacetamide dihydrochloride (56, R = H) with a,0-dicarbonyl compounds to give 2-amino-3-carbamoylpyrazines (57, R = H). 

Methylglyoxal and phenylglyoxal gave exclusively 5-substituted-2-amino-3-carbamoylpyrazines. This reaction was extended to aminoacetamidine by Pitre and Boveri (376), to give a series of 2-aminopyrazines, and to a-(substituted amidino)-a-aminoacetamide monohydrochlorides by Keir et al. (379) to provide 3-(substituted amino)-2-carbamoylpyrazine (57). 

Tetramethyl-2,4,5,7-tetraoxo-1,2,3,4,5,6,7,8-octahy dropyrim ido[5,4.g ]-pteridine 10-oxide NaOH 3,5 -Bismethy lamino-2,6-bismethylcarbamoylpyrazine 1-oxide and 2-carboxy-3,5-bismethylamino-6miethyl-carbamoylpyrazine 1-oxide 462... 

Homolytic amidation of pyrazine to 2-carbamoylpyrazine can be effected in > 80% yield by using concentrated sulfuric acid with carbamoyl radicals ( CONH2) generated from the action of hydrogen peroxide and ferrous sulfate on formamide (611). 

Cyano-6-methylaminopyrazine was also prepared from the chloro compound with methylamine hydrochloride and sodium hydroxide in aqueous dioxane (945) and 2-cyano-6-(2, 2 -dimethylhydrazino)pyrazine was prepared similarly (945). 2-Chloro-6-cyanopyrazine with methanol (and similarly with ethanol) and triethylamine gave 2-methoxy-6-(C-methoxyformidoyl)pyrazine (32) [see Section 5D(2)], and 2-chloro-6-carbamoylpyrazine with concentrated aqueous ammonia at 170-175° gave 2 -amino-b-carboxypyrazine (744). 2-Chloro-3-cyano-5,6-diphenylpyrazine with ammonium hydroxide and potassium iodide formed 2-amino-3-carbamoyl-5,6-diphenylpyrazine, but on fusion with ammonium acetate it gave 2-amino-3-cyano-5,6-diphenylpyrazine (848). 

Amino-5-bromo-3-carbamoylpyrazine heated with trifluoroacetamide and sodium ethoxide (or butoxide) gave 6-ethoxy(or butoxy)-4-hydroxy-2-trifluoro-methylpteridine (49) (987) and 2-chloro-3-pyridiniopyrazine chloride with methoxide ion gave 2,3-dimethoxypyrazine (765). 2-Amino-3-bromo-5-phenyl-pyrazine with sodium methoxide in methanol at 134° for 8 hours formed 2-amino-3-methoxy-5-phenylpyrazine (365a) and 3-bromo-2-hydroxy-5-phenylpyrazine similarly treated gave 2-hydroxy-3-methoxy-5-phenylpyrazine (365a). 

Aminopyrazines may be prepared from carbamoylpyrazines by the Hofmann degradation. Gabriel and Sonn (397) first prepared 2-aminopyrazine from 23-dicarbamoylpyrazine with potassium hypobromite through 2-amino-3-carboxy-pyrazine, which was decarboxylated when heated above its melting point (or in refluxing nitrobenzene) (397, 477). 2,3-Dicarbamoylpyrazine with 2 mol of... 

Aminopyrazines may be acetylated under a variety of conditions that mostly use acetic anhydride alone or in admixture with acetic acid, pyridine, or perchloric acid to give the following acetamidopyrazines (with reaction conditions) 2-acetamido-3-carbamoylpyrazine (acetic anhydride-acetic acid at I007l0h) (1175) ... 

Urethanes may be prepared from azidocarbonyl compounds by heating with anhydrous alcohols [see Section 1A(6)]. In this way 2,5-bisazidocarbonylpyrazine (with benzyl alcohol at 180-220°) gave 2,543is-Af-benzyloxycarbonylaminopyrazine (5) (1176) 2-azidocarbonyl-5-carbamoylpyrazine (at 150°) gave 2-A -benzyloxy-carbonylamino-5-carbamoylpyrazine (676, 1249) 2-azidocarbonyl-5-ethoxy-... 

Bis(azidocarbonyl)pyrazine at reflux with ethanol gave 2,5-bis(ethoxy-carbonylamino)pyrazine (1172) 2-carbamoylpyrazine when subjected to the Hofmann degradation gave the sodium salt of 2-carboxyaminopyrazine (which on acidification gave 2-aminopyrazine) (1171). 

Aminopyrazine 1-oxide has been prepared from 3-carbamoylpyrazine 1-oxide with sodium hypobromite (108, 547a), and the interaction of iminodiacetonitrile ... 

Diamino-3-carboxy-5-chloropyrazine in dimethyl sulfoxide (a) with N,N dicyclohexylcarbodiimide gave 2,6-diamino-3-chloro-5-(2, 5 -dioxopyrrolidin-l ylcarbonyOpyrazine ( ) (962), (6) with dicyclohexylcarbodiimide (and 2-hydrazino pyrimidine) gave 2,6-diamino-3-chloro-5-(A -cyclohexyl-V-cyclohexylcarbamoyl) carbamoylpyrazine (1331), and (c) as its triethylamine salt with V-ethyl-5-phenyl... 

Amino-5-carboxypyrazine in anhydrous dimethylformamide with triethyl-amine and ethyl chloroformate and then diethyl glutamate and stirred at room temperature gave 2-amino-5-(l, 3 -diethoxycarbonylpropyl)carbamoylpyrazine (24) (1244). Similarly a mixture of 2-carboxypyrazine and triethylamine in methylene dichloride with ethyl chloroformate and morpholine gave 2-( -morpholinocarbonyl)-pyrazine (1351). 2-Carboxy-3-hydroxypyrazine refluxed with phosphorus tris(A-methylanilide) in toluene gave 2-hydroxy-3-(A-methyl-A-phenyIcarbamoyl)pyrazine (1055), and 2-hydroxy-3-(A -methyl-A -p-tolylcarbamoyl)pyrazine was prepared similarly (1055). Tetracarboxypyrazine heated with sulfur tetrafluoride (SF4) at 150° gave tetra(trifluoromethyl)pyrazine (899). 

Many carbamoylpyrazines and related compounds such as IV-hydroxyamides (hydroxamic acids), hydrazides, cyanamides, guanidinocarbonyl-, guanidino-carbamoyl-, and ureidocarbonylpyrazines have been prepared from pyrazinecarboxylic esters. The amides were usually prepared with ammonia in methanol (or other alcohols) but also under other conditions. 

CARBAMOYLPYRAZINES (AMIDES) AND RELATED COMPOUNDS (HYDRAZIDES, AZIDES, ETC.)... 

Carboxy-3-hydroxypyrazine refluxed with phosphorus tri(Af-methylanilide) in toluene gave 2-hydroxy-3-(A -methyl-A -phenyl)carbamoylpyrazine, and 2-hydroxy-... 

Preparations of carbamoylpyrazines and related compounds by primary syntheses have been described in Chapters II.IB (192, 215, 234), II.IJ (298), II.IK (301), II.2 (347, 361, 365a, 369-375, 378-379, 382), II.5 and 11.9 (505), and further data were given in Section VIII.1A(1). Dehydrogenation of 2-carbamoylpiperazine in a current of nitrogen over palladium-charcoal at 290-305° gave 2-carbamoylpyrazine (1391). 

The crystal structure of 2-carbamoylpyrazine has been determined the pyrazine ring is completely planar, with mean C-N = 1.348 and C-C = 1.383 A, and made an angle about 5° to the amide group (C-0 = 1.244 and C-N = I.3I2 A) (1395). Investigations for 2-carbamoylpyrazine have been made of the heat of sublimation (1396), heat of fusion (1397), and solubilities in various solvents (1398) and the results correlated. The pA of 2-carbamoylpyrazine has been determined as — 0.5 (140). 

The antitubercular activity of 2-carbamoylpyrazine and biological activity of pyrazines generally has been mentioned in Section 1.4. Certain pyrimidinyl derivatives of 2-carbamoylpyrazine have been shown to have lower toxicity and rather greater in vitro activity against Mycobacterium tuberculosis than 2-carbamoylpyrazine (1388), and the antitubercular activity of some extranuclear )V-substituted carbamoylpyrazines also showed a higher activity than 2-carbamoylpyrazine (1201). When tested on mice in vivo, 2-carbamoyl-5-methoxypyrazine and 2-hydrazino-carbonylpyrazine had less antitubercular activity than did 2-carbamoylpyrazine (1098) the antitubercular activities in a series of hydrazinocarbonyl-, carbamoyl-, and thiocarbamoylpyrazines have been examined and compared (1399). 

Carbamoylpyrazine in dogs and humans is hydrolyzed to 2-carboxypyrazine and then converted to 2-carboxy-5-hydroxypyrazine (1400) and a combined gas chromatographic-mass spectroscopic technique has been described for the simultaneous determination of 2-carbamoylpyrazine, 2-carboxypyrazine, and 2-carboxy-... 

Pyrazinamide is one of the most powerful drugs available for the inhibition of urate excretion in man, consistently providing a 80-90% reduction in the renal clearance of uric acid (1401, 1403). 2-Morpholinocarbonylpyrazine and its 6-methoxy derivative are claimed to have antidiabetic activity (948, 949, 1351, 1387, 1404), and some 2-(p-ureidosulfonylphenethylcarbamoyl)pyrazines have been shown to have hypoglycemic activity in mice (1405). The effect of 2-amino-3-hydroxy-carbamoylpyrazine on DNA synthesis by Erlich ascites tumor cells in vitro has been investigated (1406) as well as the inhibition by 2-amino-3-hydroxycarbamoylpyrazine on L-histidine carboxylyase (1407) many 2-hydroxyimidazo[4,5-6]pyrazines (prepared from 2-amino-3-hydrazinocarbonylpyrazines with nitrous acid) are potent hypotensive agents in animals (880,891,963,1181). 

Carbamoylpyrazines with various dehydrating agents afford cyanopyrazines. Ellingson et al. (1175) first dehydrated 2-amino-3-carbamoylpyrazine with phosphorus pentoxide in refluxing pyridine to 2-amino-3-cyanopyrazine this... 

Carbamoylpyrazines have been hydroxymethylated with formaldehyde and potassium carbonate, and aminomethylated with formaldehyde and amine. In this way the following have been prepared 2-Af-hydroxymethylcarbamoylpyrazine (138) 2W-(diethylaminomethyl)carbamoylpyrazine (1413-1416) 2W-(morpho-linomethyl)carbamoylpyrazine (1414, 1416) and 2-A -[piperidino(pyrrolidino or other amino)methyl]carbamoylpyrazines(1414,1416). 2-7V-(Diethylaminomethyl)-carbamoylpyrazine refluxed with morpholine afforded 2-A -(morpholinomethyl)-carbamoylpyrazine (1415), and 2-carbamoylpyrazine with TV-(morpholinomethyl)-benzenesulfonamide gave 2-7V-(morpholinomethyl)carbamoylpyrazine (1417). 

Carbamoylpyrazine refluxed with acetic anhydride gave 2-)V-acetylcarbamoyl-pyrazine (138,1418) and 2,5-bis-A -acetylcarbamoylpyrazine was prepared similarly (672). 2,3-Dicarbamoylpyrazine heated in a vacuum gave the imide of 2,3-dicarboxy-pyrazine (397). 

Carbamoylpyrazine was methylated to 3-carbamoyl-l -methylpyrazinium iodide by methyl iodide in methanol at reflux (138) and by methyl iodide in dimethyl sulfoxide at room temperature (666) under the latter conditions the rate of methylation relative to pyrazine was 0.53 (666). 3-Carbamoyl-l-methylpyrazinium iodide reacted with liquid ammonia at — 40° to give 2-amino-5-carbamoyl-l-methyl-1,2-dihydropyrazine (46) (609). With nitromethide ions in liquid ammonia, none of the carbon addition reaction was found (721), but with ethanethiolate ion in liquid ammonia it gave 5-carbamoyl-2-ethylthio-l-methyl-1,2-dihydropyrazine (721). 2-(4 -Morpholino)carbonylpyrazine with methyl iodide gave 3-(4 -morpholino)-carbonyl-1-methylpyrazinium iodide (870). 

---